17-oxygenated 2beta-fluoro-5alpha-androstan-3-ones and intermediates thereto



United States Patent 3,104,244 I7-QXYGENATED ZB-FLUURO-Sa-ANDRUSTAN- S-UNES AND lNTE a2; DIATES TI-ERETU Raymond E. Counsell, Skokie, and Paul D. Klimstra, 5 Northbrook, lib, assignors to G. D. Searle & 60., Chicago, ill, a corporation of Delaware No Drawing. Filed Mar. 16, 1962, Ser. No. 180,335 Claims priority, application Great Britain June 5, 1961 9 Claims. (Cl. 260-6975) 10 The present invention relates to Zfl-fiuoro steroids and, more particularly, to l7-oxygenated ZB-fluoro-Sa-androstan-3-ones of the structural formula CH3 CH wherein X represents a carbonyl, B-hydroxymethylene, or ,B-(lower alkanoyDoxymethylene radical. 2 Novel intermediates useful in the manufacture of those 3-keto substances are represented by structural formula OR CH3 wherein X is a carbonyl, B-hydroxymethylene, or ,B-(lower alkanoyl)oxymethylene group. Reaction of those substances With anhydrous hydrogen fluoride in an organic solvent medium produces the corresponding 2f3,3oc-fl110r0 hydrins. For example, 20,3a-epoxy-5'a-androstan-175- ol 17-acetate in tetrahydrofuran containing chloroform is allowed to react with anhydrous hydrogen fluoride to afford 17B-acetoxy-2/i-fluoro-5a-androstan-3a-ol. Esterifi- 3,104,244 Patented Sept. 17, 1963 cation of this 3a-hydroxy compound with acetic anhydride in pyridine produces Zfl-fluoro-Sa-andrOStane-Zaa,17,8-diol 3,17-diacetate, which is hydrolyzed with aqueous sodium carbonate in methanol to produce the free 30,l7B-di0l. This diol is converted to 2/3-fluoro-5zx-androstane-3,17- dione by oxidation, suitably with aqueous chromic acid. The aforementioned l7/3-acetoxy-2fl-fiuor0-5a-androsta-n- 3oz-0l can be oxidized, for example with the chromium trioxide-sulfuric acid reagent to yield -acetoxy-2fifluoro-5a-androstan-3-one. Hydrolysis, typically with aqueous sodium carbonate in methanol, affords Zfi-fluoro- 17,8-hyd1'oxy-5wandrostan-B-one, which is oxidized with chromium trioin'de in aqueous sulfuric acid to yield 2(3- fluoro-5a-androstane-3,17-dione. An alternate route to this 3,17-dione utilizes 2a,3m-epoxy-5a-androstan-17-one as starting material. Reaction with anhydrous hydrogen fluoride in rtetrahydrofuran-chloroform affords Zfl-fluoro- 3u-hydroxy-5o-androstan-17-one, which is allowed to react with the aforementioned oxidizing mixture, consist ing of chromium trioxide in aqueous sulfuric acid, to yield the instant Zfi-fluoro-Sa-androstane-3,l7-dione.

20,3a-epoxy-Sa-androstan-l75-ol 17,8-acetate, described above, is hydrolyzed, suitably by means of methanolic aqueous sodium carbonate to yield 2a,3a-epoxy-5a- Treatment of that substance with an alkanoic acid anhydride in pyridine affords the 20,3aepoxy-5e-androstan-17fi-ol l7-(lower alkanoates), which are converted to the corresponding Uri-(lower alkanoyl) oxy compounds of this invention by the processes described above. Reaction of that 17B-ol with propionic anhydride and pyridine, for example, affords 20,3aepoxy-Swandrostan-175-01 17-propionate.

The 3-keto compounds of this invention are useful as a result of their valuable pharmacological properties. They are, for example, anti-estrogenic agents as is evidenced by their ability to inhibit estrogen-stimulated iological responses. They are particularly useful in view of the absence of potent anabolic and androgenic side-effects. The 3a-ols and 3a-(lower alkanoates) of this invention are useful as intermediates, as is apparent from the above disclosure.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only, and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centigrade C.). Quantities of materials are expressed in parts by Weight unless otherwise noted.

Example 1 To a solution of 10.4 parts of anhydrous hydrogen fluoride in 13.5 parts of chloroform containing 16.9 parts of tetnahydrofuran is added dropwise with stirring, at about 20, an ice-cold solution of 5.6 pants of 20:,3aepoxy-17(3-hydroxy-5a-androstan-175-01 17-aceta-te in 52.5 parts of chloroform. This addition requires about two hours. Stirring is continued for about one hour longer, while the solution is allowed to warm to room temperature. The reaction mixture is then rapidly stirred and cautiously poured into ice-cold aqueous potassium oarbonate. This aqueous mixture is extracted with chloroform, and the aqueous layer is separated and extracted again with chloroform. The combined extracts are washed with Water, dried over anhydrous potassium carbonate containing decolorizing carbon, and stripped of solvent at reduced pressure to afford a solid residue' This residue is chromatographed on silica gel, then eluted with ethyl acetate in benzene to afford pure 17B- acetoxy-2e-fluoro-5a-androstan-3e-ol, which melts at about 2045-2055 and displays an optical rotation of +12 in chloroform. It is represented by the formula 0 C 0 CH3 CH3(\ F Example 2 To a solution of one part of 17fl-acetoxy-2B-fluoro-5aandrostau-Sa-ol in 16 days of acetone is added dropwise an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid, until a slight excess of the oxidant is present, as is evidenced by the persistence of the brown color of the reagent. Approximately 0.2 part of isopropyl alcohol is then added to destroy the excess reagent and the supernatant liquid is decanted from the resulting precipitated salts, then is poured into a mixture of ice and water. The resulting precipitate is collected by filtration, washed with Water, and recrystallized from acetonehexane to affio-rd pure 17fl-acetox Jfi-fluoro-Sa-androstan-S-one, M.P. about 153-154; [a] =|-38. It is represented by the structural formula OCOCHs Example 3 To a solution of parts of 175'acetoxy-2B-fiuoro-5aandrostan-3-one in 400 parts of methanol is added a solution of 2 parts of sodium carbonate and 50 parts of water, and this reaction mixture is heated at 50-60 for about 5 minutes, then is cooled. The precipitate which forms is collected by filtration and dried to yield 2fl-fluoro-l7fihydroxy-5a-androstan-3-one of the formula OH CE? I F Example 4 The reaction .of one part of 2 3-fluoro-17fihydroxy-5uandrostan-3-one with the chromium trioxide-sulfuric acid aqueous reagent described in Example 2, by the procedure of that example, results in 2f3-luoro-5ot-androstane- 4 3,17-dione, M.P. about 142-143"; [a] =+lZ3 (chloroform). This compound is represented by the formula Example 5 A mixture of 1.6 parts of 17/3-acetoxy-2{3fluoro-5a-androstan-Zla-ol, 8.1 parts of acetic anhydride, and 10.5 parts of pyridine is stirred for about 16 hours at room temperature, then is poured into a mixture of ice and Water. The resulting precipitate is collected by filtration, then is Washed successively with dilute hydrochloric acid and Water, dried, and recrystallized from acetone'hexane to produce 2,8-fluoro-5wandrostane-Ba,17B-diol 3,l7-diacetate, M.P. about -177"; [a] =-l-37 (chloroform). It is represented by the structural dormula OCOCII; CII;

omcoo-- This diacetate can be obtained also by substituting 1.4 parts of 2e-fluoro-5a-androstane6a,17,6-diol in the process of this example.

Example 6 By substituting 5.65 parts of 2/3-fiuoro-5a-androstane- 3a,17fi-diol 3,17-diacetate and otherwise proceeding according to the processes described in Example 3, 25- fiuoro-5u-androstane-3e,175-diol, M.P. about 242-244, is obtained. It is represented by the tformula OH CH? Example 7 The substitution of one part of 2,8-tluoro-5wandrostane-3tx,17fi-diol in the procedure of Example 2 results in 2,8-fiuoro-5a-androstane-3,17-dione, M.P. about 142- 143, identical with the product of Example 4.

Example 8 Into a mixture of 33.7 parts of ltetrahydrofuran in 21 parts of chloroform, cooled to about -20, is bubbled 20.8 parts of anhydrous hydrogen fluoride. This solution is cooled and stirred while a solution of 12 parts of 2a,3a-epoxy-5a-androstan-3-one in 96 parts of chloroform is added dropwise over a period of about 2 /2 hours, during which time the addition of hydrogen fluoride is continued. After completion of the addition, the reaction mixture is stirred for about 1 /2 hours longer while it is Warming to room temperature. This solution is then poured into excess concentrated aqueous potassium carbonate, and the aqueous mixture is extracted with chloro- OH: H

Example 9 To a solution of one part of 2fl-1luoro-3a-hydroxy-5aandrostan-l7-one in 20 parts of isopropyl alcohol is added a solution of 0.7 part of sodium borohydride in 4 parts of isopropyl alcohol containing 1.5 parts of Water. This reaction mixture is stirred at room temperature (for about 3 hours, then is diluted with ice and Water. The resulting precipitate is collected by filtration, washed with Water, dried, and recrystallized from aqueous ethanol to afford pure 2B-fluoro-5a-androstane-3a,17B-diol, M.P. about 242-244", It is identical with the product of Example6.

Example To a cooled solution of 4 parts of 25-lluoro-3a-hydrQXy-Sa-androstan-17-.one in 40 parts oi acetone is added dropwise, with rapid stirring, a slight excess of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The solution is poured into an ice-water mixture and the resulting oily product is extracted into methylene chloride. The organic extract is Washed with water, dried \OVI' anhydrous potassium carbonate containing decolorizing carbon, and stripped of solvent in vacuo to afford an oil which solidifies on standing. Recrystallization from aqueous methanol yields pure 25-fluoro-5aandrostane-3,17-dione, melting at about 142143 and displaying an optical rotation in chloroform of +123". It is identical with tthe product of Example 4.

Example 11 The substitution of 9.5 parts of 2a,3a-epoxy-5a-androstan-l7B-ol 17- acetate in the procedure of Example 3 results in 2a,3a-epoxy-5a-androstan-175-01, MP. about 183-184.

Example 12 A mixture of one part of 2a,3a-epoxy-5a-androstan- 175-01, 10 parts of propionic anhydride, and 20 parts of pyridine is stored at room temperature for about 3 hours, then is poured into a mixture of ice and Water. The resulting aqueous mixture is extracted with benzene, and the organic extract is washed successively with water and dilute hydrochloric acid, dried over anhydrous potassium carbonate, and shipped of solvent at reduced pressure to yield 2a,3oi-epoxy-5a-androstan-17,8-01 17-propionate.

Example 13 The substitution of 5.85 parts of 2a,3a-epoxy-5a-androstan-17fl-ol 17-propionate in the procedure out Example 6 1 results in 2,8-fiuoro-17,B-propi0noxy-Sa-androstan-3a-ol of the structural formula 0 o 0 011201 13 CH3 I-IO- Example 14 By substituting one part of 2/3-fluoro-17fi-propionoxy- 5 a-androstan-3a-ol and otherwise proceeding according to the processes of Example 2, 2,8-fiuoro-17fi-propionoxy-5aandrostan-3-one of the structural formula 0 C O CHZCHS CH3 is obtained.

Example 15 The hydrolysis of 10.4 parts of 2,8-fluoro-17B-propionoxy-5oc-androstan-3-one by the processes described in Example 3 aflFor-ds Z p-fluoro-17B-hydroxy-5a-androstan-3- one, identical with the product or" that example.

Example 16 The reaction of 1.67 parts of ZB-fluoro-lW-propionoxy-5ot-arrdrostan-3a-ol with 10.3 parts of propionic anhydride according to the procedure of Example 5 results in 2fi-fluoro-5a-androstane-3a,17,6 diol 3,17-dipropionate of the structural formula 0 C O CHzCHs CH CHBCHZO 0 0-- What is claimed is:

1. A compound of the formula wherein R is selected from the group consisting of hydrogen and lower alkanoyl radicals.

7 2. 17fl-acetoxy-2fi-flu0ro-5a-androstan-3-one. A Compound of the formula- 3. 2;8-fiuoro-l7/3-hydroxy-5a-androstan-3-one. 4. ZB-fiuoro-a-an'drostane-3,17-di0ne. 0 00 (lower alkyl) 5. A compound of the formula CHI CH; F I

OR CH3 10 3 H I 9. 17p-acetoxy-Zfi-fluoro-Swandrostan-3a-ol.

F- References Cited in the file of this patent R0 UNITED STATES PATENTS 3,009,934 Counsell et a1 Nov. 21, 1961 OTHER REFERENCES 20 Dor'fman et al.: Androgens, John Wiley & Sons, Inc., New York, New York, pp. 590, 1956 (pages 98, 99, 101, 104 124). wherem R 15 selected from the group conslstmg of hydroa gen and lower alkanoyl radicals lggloathan et al.. J.A.C.o. 82, 1436-1437, March 20,

6. 2,8-fiuoro-5 a-androstane-3cc,17B-diol.

7. 2fi-fluoro-Sa-androstanea,17fi diol 3,17 diacetate. Kissman et 'Q' 2312-2317 May 1960' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Noe 3,10%244 September 17, 1963 Raymond E. Coun sell, et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2 line 28, for "(lower alkanoyl) read (lower alkanoy1)- column 3, line 26, for "16 days" read 16 parts column 7, lines 8 to lo the lower portion of the formula should appear as shown below instead of as in the patent:

lines 2 to l2 the lower portion of the formula column 8,

instead of as in the patent:

should appear as shown below Signed and sealed this 5th day of May 1964.

ERNEST W, SWIDER Commissioner of Patents Attesting Officer 

1. A COMPOUND OF THE FORMULA
 5. A COMPOUND OF THE FORMULA 